Specific interactions of cells within the extracellular matrix are critical for the normal function of organisms. Alterations of the extracellular matrix are carried out by a family of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs). The alterations are carried out in various cellular processes such as organ development, ovulation, fetus implantation in the uterus, embryogenesis, wound healing, and angiogenesis.
Twenty-six different MMPs are currently known. MMPs consist of five major groups of enzymes: gelatinases, collagenases, stromelysins, membrane-type MMPs, and matrilysins. The activities of MMPs in normal tissue functions are strictly regulated by a series of complicated zymogen activation processes and inhibition by protein tissue inhibitors for matrix metalloproteinases (TIMPs). Excessive MMP activity, when the regulation process fails, has been implicated in cancer growth, tumor metastasis, angiogenesis in tumors, arthritis and connective tissue diseases, cardiovascular disease, inflammation, autoimmune diseases, respiratory diseases, and neurological disorders.
Increased levels of activity for the human gelatinases MMP-2 and MMP-9 have been implicated in several metabolic processes, for example, cancer, tumor metastasis, angiogenesis in tumors, arthritis and connective tissue diseases, cardiovascular disease, inflammation, autoimmune diseases, respiratory diseases, and neurological disorders. Gelatinases are also of particular importance for both female ovulation and implantation of zygotes in the womb (for example, see U.S. Pat. No. 6,703,415). As a result, selective inhibitors of MMPs are highly sought.
Several competitive inhibitors of MMPs are currently known. These inhibitors of MMPs take advantage of chelation to the active site zinc for inhibition of activity. Because of this general property, these competitive inhibitors for MMPs are often toxic to the host, which has been a major impediment in their clinical use.
Accordingly, there is a current need for new inhibitors of MMPs. Such inhibitors would be useful to treat or prevent cancer, tumor metastasis, angiogenesis in tumors, contraception, arthritis and connective tissue diseases, cardiovascular disease, inflammation, autoimmune diseases, respiratory diseases, or neurological disorders. Also needed are inhibitors that exhibit selectivity for one or more specific MMPs. Such inhibitors will preferably not include negative long-term side-effects.